Novel 3-(1-acetyl-5-(substituted-phenyl)-4,5-dihydro-1H-pyrazol-3-yl)-7- fluoro-2H-chromen-2-one derivatives: Synthesis and anticancer activity

Article abstract of DOI:10.2174/157018010792929540

A series of novel coumarin derivatives containing 4,5-dihydropyrazole moiety as potential telomerase inhibitors were synthesized. The bioassay tests showed that compound 3b exhibited potentially high activity against human gastric cancer cell SGC-7901 wit

Full text of DOI:10.2174/157018010792929540

640
Letters in Drug Design & Discovery, 2010, 7, 640-643
Novel 3-(1-acetyl-5-(substituted-phenyl)-4,5-dihydro-1H-pyrazol-3-yl)-7-
fluoro-2H-chromen-2-one Derivatives: Synthesis and Anticancer Activity
Zheng-Yu Caia, Yang Yanga Xin-Hua Liu*,a and Xing-Bao Qib
aSchool of Chemistry and Chemical Engineering, Anhui University of Technology, Maanshan, 243002, P. R. China
bSchool of Pharmacy, China Pharmaceutical University, Nanjing 210009, China
Received April 01, 2009: Revised July 20, 2010: Accepted August 04, 2010
Abstract: A series of novel coumarin derivatives containing 4,5-dihydropyrazole moiety as potential telomerase inhibi-
tors were synthesized. The bioassay tests showed that compound 3b exhibited potentially high activity against human gas-
tric cancer cell SGC-7901 with IC50 value was 2.98±0.16. Docking simulation was performed to position compound 3b
into the telomerase (3DU6) active site to determine the probable binding model. The result shows that some coumarin
containing 4,5-dihydropyrazole moiety can combine well with the telomerase active site and may have use as potential te-
lomerase inhibitors.
Keywords: Coumarin, Dihydropyrazole, Molecular Docking, Antitumor Agent.
INTRODUCTION
dihydropyrazole derivatives [10-11]. Based on above reports,
we considered the possibility of introducing heterocyclic 4,5-
dihydropyrazole moiety into the parent coumarin unit to de-
sign novel structures with enhanced anticancer activities.
Since there are only a very few systematic reports on the
synthetic methodology and evaluation of anticancer activities
of these compounds, we prepared herein a series novel cou-
marin derivatives containing 4,5-dihydropyrazole moiety and
tested their activities against human gastric cancer cell SGC-
7901 and human liver cancer cell Hep-G2. In order to eluci-
date the potential mechanism by which the title compounds
induce anticancer activity, docking simulation was per-
formed to position selected compounds into the active site of
telomerase 3DU6.
Telomerase remains active in the early stages of life
maintaining telomere length and the chromosomal integrity
of frequently dividing cells. It turns dormant in most somatic
cells during adulthood [1]. In cancer cells, however, telom-
erase gets reactivated and works tirelessly to maintain the
short length of telomeres of rapidly dividing cells, leading to
their immortality [2]. The essential role of telomerase in can-
cer and ageing makes it an important target for the develop-
ment of therapies to treat cancer and other age-associated
disorders. Telomere and telomerase are closely related to the
occurrence and development of human gastric cancer and
human liver cancer [3].
Coumarins are present in natural and synthetic com-
pounds possessing biological activity. Some of them have
cytostatic properties and the others have cytotoxic activity
[4]. Two naturally occurring coumarins have been found to
exhibit cytotoxicity against a panel of mammalian cancer
cell lines [5]. In view of their importance as drugs, biologi-
cally active natural products, and in other related applica-
tions, extensive studies have been carried out on the synthe-
sis of coumarin compounds in recent years. On the other
hand, many literatures discussed the antitumor activity of
pyrazole derivatives [6, 7]. Furthermore, 3,4-dihydro-
pyrazole, a small bioactive molecule, is a prominent struc-
tural motif found in numerous pharmaceutically active com-
pounds. Many 3,4-dihydropyrazole-based derivatives have
shown several biological activities as seen in CB1 antagonist
[8], and tumor necrosis inhibitor [9]. Many of them are cur-
rently being tested and/or clinically evaluated for new drug
discovery.
METHODS
1. Instruments
The melting points of the products were determined on
an XT-4 binocular microscope (Beijing Tech Instrument
Co.,China) and are not corrected. The 1H NMR and 13C
NMR spectra were recorded on a Varian INOVA300 (300
MHz) pulse Fourier-transform NMR spectrometer in CDCl3
using tetramethylsilane as an internal standard. ESI mass
spectra were obtained on a Mariner System 5304 mass spec-
trometer. Elemental analysis was performed on an Elementar
Vario-III CHN analyzer. Column chromatographic opera-
tions were performed on silica gel GF254. The reagents were
all of analytical reagent-grade or chemically pure. All sol-
vents were dried, deoxygenated and redistilled before use.
2. Syntheses
In an effort to synthesize novel 3,4-dihydropyrazole het-
erocyclic systems with potential biological activity, our
group has recently reported on the activity of some 3,4-
The synthesis of compound 1 (Scheme 1) started from 4-
fluoro-2-hydroxybenzaldehyde and catalyzed by piperazine
at 25 oC was added methyl-acetoacetate. Claisen-Schmidt
condensation 3-acetyl-7-fluoro-2H-chromen-2-one and sub-
stituted-benzaldehyde using mild catalyst piperidine, by fol-
lowing a reported method [10], proved to be an efficient al-
ternative for the synthesis of ꢀ, ꢁ unsaturated ketone 2. To a
*Address correspondence to this author at the School of Chemistry and
Chemical Engineering, Anhui University of Technology, Maanshan,
243002, P. R. China; Tel: +86 555 2311551; Fax: +86 555 2312552;
E-mail: xhliuhx@163.com
1570-1808/10 $55.00+.00
© 2010 Bentham Science Publishers Ltd.

Synthesis and Anticancer Activity
Letters in Drug Design & Discovery, 2010, Vol. 7, No. 9 641
O
O
O
O
CH3
(II)
H
(I)
H3C
O
CH3
F
O
O
O
F
OH
1
CH3
O
O
N
N
R
(III)
R
F
O
O
O
F
2
3
R = 4-Me (a), 4-OH (b), 2-Cl (c), H (d), 2,4-Cl (e), 2-Br (f), 2-NO2 (g)
Scheme 1. Synthesis of title compounds. Reagent and conditions: (I) piperzine, 25 oC, 1 h. (II) substituted benzaldehyde, piperidine, ethanol,
reflux, 8 h. (III) 60% NH2-NH2.H2O, 98% CH3COOH, reflux, 3 h.
solution of ꢀ, ꢁ unsaturated ketone 2 (10 mmol) in acetic
acid (20 ml) was added hydrazine monohydrate (40 mmol)
and the reaction mixture was refluxed for 3 h. The mixture
was cooled, adjusted pH to 7 with 10% Na2CO3 solution,
poured into crush ice, and allowed to stand at room tempera-
ture over night. The product was collected by filtration and
the crude residue was purified by chromatography on SiO2
(acetone/petroleum, V:V=3:1) to give title compounds 3
(Scheme 1) as colorless solids.
18.0 Hz, pyrazole, 4-Hb), 5.65 (1H, dd, J 12.0 and 4.0 Hz,
pyrazole, 5-H), 6.76-7.16 (6H, m, C6-H, C8-H, ArH), 7.42
13
(1H, d, J 8.4 Hz C5-H), 8.28 (1H, s, C4-H); C NMR (75
MHz, CDCl3): ꢀ 24.5, 39.2, 56.4, 110.2, 113.3, 118.7, 124.0,
127.5, 128.2, 128.7, 128.9, 129.1, 132.1, 134.3, 144.9, 152.2,
156.8, 160.8, 163.7, 169.9; ESI-MS: 384.1 (C20H14ClFN2O3,
[M+H]+). Anal. calcd for C20H14ClFN2O3: C 62.43, H 3.67,
N 7.28; found C 62.07, H 4.01, N 7.44.
3d:
3-(1-acetyl-5-phenyl-4,5-dihydro-1H-pyrazol-3-yl)-7-
3a: 3-(1-acetyl-5-p-tolyl-4,5-dihydro-1H-pyrazol-3-yl)-7-
fluoro-2H-chromen-2-one
fluoro-2H-chromen-2-one
Colorless crystals; yield: 76%, m.p., 178-179 oC. 1H
NMR (CDCl3, 300 MHz): ꢀ 2.31 (3H, (3H, s, -Me), 3.42
(1H, dd, J 18.0 and 4.0 Hz, pyrazole, 4-Ha), 3.76 (1H, dd, J
12.0 and 18.0 Hz, pyrazole, 4-Hb), 5.65 (1H, dd, J 12.0 and
4.0 Hz, pyrazole, 5-H), 6.70 (1H, s, C8-H), 6.84 (1H, d, J 8.3
Hz, C6-H), 7.00-7.17 (5H, m, ArH), 7.41 (1H, d, J 8.4 Hz C5-
H), 8.18 (1H, s, C4-H); 13 C NMR (75 MHz, CDCl3): ꢀ 24.5,
39.8, 57.2, 110.7, 113.4, 119.0, 124.2, 126.6, 127.7, 128.0,
129.1, 134.5, 145.2, 152.3, 156.7, 160.9, 163.8, 170.0; ESI-
MS: 351.1 (C20H15FN2O3, [M+H]+). Anal. calcd for
C20H15FN2O3: C 68.57, H 4.32, N 8.00; found C 68.83, H
4.70, N 8.38.
Colorless crystals; yield: 70%, m.p., 186-187 oC. 1H
NMR (CDCl3, 300 MHz): ꢀ 2.27 (3H, s, -Me), 2.47 (3H, s, -
Me), 3.39 (1H, dd, J 18.0 and 4.0 Hz, pyrazole, 4-Ha), 3.82
(1H, dd, J 12.0 and 18.0 Hz, pyrazole, 4-Hb), 5.45 (1H, dd, J
12.0 and 4.1 Hz, pyrazole, 5-H), 6.77 (1H, s, C8-H), 6.82
(1H, d, J 8.4 Hz, C6-H), 7.10-7.15 (4H, m, ArH), 7.37 (1H,
d, J 8.4 Hz C5-H), 8.32 (1H, s, C4-H); 13 C NMR (75 MHz,
CDCl3): ꢀ 24.2, 25.1, 40.3, 56.2, 110.4, 111.7, 118.3, 124.0,
127.4, 128.5, 128.9, 134.2, 138.0, 142.1, 152.5, 157.2, 161.6,
164.3, 169.7; ESI-MS: 365.1 (C21H17FN2O3, [M+H]+). Anal.
calcd for C21H17FN2O3: C 69.22, H 4.70, N 7.69; found C
68.96, H 4.51, N 8.01.
3e:3-(1-acetyl-5-(2,4-dichlorophenyl)-4,5-dihydro-1H-
pyrazol-3-yl)-7-fluoro-2H-chromen-2-one
3b: 3-(1-acetyl-5-(4-hydroxyphenyl)-4,5-dihydro-1H-
pyrazol-3-yl)-7-fluoro-2H-chromen-2-one
Colorless crystals; yield: 62%, m.p., 200-202 oC. 1H
NMR (CDCl3, 300 MHz): ꢀ 2.37 (3H, (3H, s, -Me), 3.48
(1H, dd, J 18.0 and 4.0 Hz, pyrazole, 4-Ha), 3.70 (1H, dd, J
12.0 and 18.0 Hz, pyrazole, 4-Hb), 5.58 (1H, dd, J 12.0 and
4.0 Hz, pyrazole, 5-H), 6.79 (1H, s, C8-H), 6.89 (1H, d, J 8.4
Hz, C6-H), 6.96-7.25 (3H, m, ArH), 7.49 (1H, d, J 8.4 Hz C5-
H), 8.29 (1H, s, C4-H); 13 C NMR (75 MHz, CDCl3): ꢀ 24.5,
39.1, 55.2, 110.3, 112.7, 118.8, 124.4, 127.1, 129.0, 130.3,
131.5, 134.4, 134.6, 134.8, 142.5, 152.7, 157.0, 161.2, 163.0,
169.9; ESI-MS: 420.2 (C20H13Cl2FN2O3, [M+H]+). Anal.
calcd for C20H13Cl2FN2O3: C 57.30, H 3.13, N 6.68; found C
56.91, H 2.84, N 6.92.
Colorless crystals; yield: 64%, m.p., 201-202 oC. 1H
NMR (CDCl3, 300 MHz): ꢀ 2.35 (3H, s, -Me), 3.30 (1H, dd,
J 18.0 and 4.1 Hz, pyrazole, 4-Ha), 3.75 (1H, dd, J 12.0 and
18.0 Hz, pyrazole, 4-Hb), 5.60 (1H, dd, J 12.0 and 4.1 Hz,
pyrazole, 5-H), 6.61-7.03 (6H, m, C6-H, C8-H, ArH), 7.39
(1H, d, J 8.4 Hz C5-H), 8.20 (1H, s, C4-H), 8.85 (1H, s, -
OH); 13 C NMR (75 MHz, CDCl3): ꢀ 24.0, 39.7, 55.5, 109.7,
112.9, 118.0, 119.3, 124.1, 129.0,129.1, 134.5, 137.2, 152.7,
157.3, 158.0, 160.2, 163.3, 169.9; ESI-MS: 367.0
(C20H15FN2O4, [M+H]+). Anal. calcd for C20H15FN2O4: C
65.57, H 4.13, N 7.65; found C 65.67, H 3.94, N 7.82.
3c: 3-(1-acetyl-5-(2-chlorophenyl)-4,5-dihydro-1H-pyrazol-
3-yl)-7-fluoro-2H-chromen-2-One
3f: 3-(1-acetyl-5-(2-bromophenyl)-4,5-dihydro-1H-pyrazol-
3-yl)-7-fluoro-2H-chromen-2-one
Colorless crystals; yield: 58%, m.p., 190-191 oC. 1H
NMR (CDCl3, 300 MHz): ꢀ 2.30 (3H, s, -Me), 3.37 (1H, dd,
J 18.0 and 4.1 Hz, pyrazole, 4-Ha), 3.68 (1H, dd, J 12.0 and
Colorless crystals; yield: 55%, m.p., 196-197 oC. 1H
NMR (CDCl3, 300 MHz): ꢀ 2.35 (3H, s, -Me), 3.31 (1H, dd,
J 18.0 and 4.1 Hz, pyrazole, 4-Ha), 3.71 (1H, dd, J 12.0 and

642 Letters in Drug Design & Discovery, 2010, Vol. 7, No. 9
Cai et al.
Table 1. Cytotoxic Activity of the Synthesized Compounds Against SGC-7901 and Hep-G2 Cell Linesa
Compound
IC50 (ꢀg/mL)b
Hep-G2
Compound
IC50 (ꢀg/mL)b
Hep-G2
SGC-7901
SGC-7901
3a
35.74±2.14
2.98±0.16
28.93±0.11
8.51±0.70
7.30±0.67
47.12±1.18
48.20±0.99
40.02±2.00
39.73±1.01
2.58±0.29
3e
22.61±0.68
23.95±0.29
38.74±1.27
7.30±0.67
40.03±1.40
49.70±0.88
39.94±1.00
2.58±0.29
3b
3f
3c
3d
3g
5-Fluorouracilc
5-Fluorouracilc
aThe data represented the mean of three experiments in triplicate and were expressed as means ±SD; Only descriptive statistics were done in the text.
bThe IC50 value was defined as the concentration at which 50% survival of cells was observed. The results are listed in the table.
cUsed as a positive control.
Negative control DMSO, no activity.
18.0 Hz, pyrazole, 4-Hb), 5.70 (1H, dd, J 12.0 and 4.0 Hz,
pyrazole, 5-H), 6.70 (1H, s, C8-H), 6.81 (1H, d, J 8.4 Hz, C6-
H), 6.99-7.44 (5H, m, C5-H, ArH), 8.11 (1H, s, C4-H); 13 C
NMR (75 MHz, CDCl3): ꢀ 24.7, 38.7, 53.2, 110.7, 112.9,
118.4, 122.6, 124.0, 127.6, 128.9, 129.9, 130.2, 132.3, 134.5,
147.0, 152.7, 156.8, 160.8, 162.9, 169.4; ESI-MS: 428.2
(C20H14BrFN2O3, [M+H]+). Anal. calcd for C20H14BrFN2O3:
C 55.96, H 3.29, N 6.53; found C 56.21, H 3.08, N 6.81.
RESULTS AND DISCUSSION
1. Biological Activity
In the screening assay studies, all the compounds 3a-g
were evaluated for their cytotoxic activity against gastric
SGC-7901 and human liver cancer Hep-G2 cell lines. Also
included was the activities of reference compound 5-
Fluorouracil. The cell was allowed to proliferate in presence
of tested material for 48 h, and the results are reported in
terms of IC50 values (Table 1). From the data presented in
Table 1, it can be concluded that title compounds displayed
certain activity against human gastric cell SGC-7901,
whereas showed relatively poor activity against the human
liver cancer Hep-G2 cell. It is obvious from the data that
compound 3b exhibited potentially high activity against the
human gastric cell SGC-7901 with IC50 value of 2.98±0.16
ꢀg/mL, exceed to that of positive control 5-Fluorouracil,
compound 3d showed anticancer activity against the human
gastric cell SGC-7901 with IC50 value of 8.51±0.70 ꢀg/mL,
comparable to that of positive control 5-Fluorouracil.
3g: 3-(1-acetyl-5-(2-nitrophenyl)-4,5-dihydro-1H-pyrazol-
3-yl)-7-fluoro-2H-chromen-2-one
Colorless crystals; yield: 60%, m.p., 214-216 oC. 1H
NMR (CDCl3, 300 MHz): ꢀ 2.32 (3H, s, -Me), 3.38 (1H, dd,
J 18.0 and 4.1 Hz, pyrazole, 4-Ha), 3.65 (1H, dd, J 12.0 and
18.0 Hz, pyrazole, 4-Hb), 5.58 (1H, dd, J 12.0 and 4.0 Hz,
pyrazole, 5-H), 6.79 (1H, s, C8-H), 6.88 (1H, d, J 8.4 Hz, C6-
H), 7.33-8.08 (5H, m, C5-H, ArH), 8.23 (1H, s, C4-H); 13 C
NMR (75 MHz, CDCl3): ꢀ 24.6, 39.1, 52.2, 110.8, 113.0,
118.6, 121.5, 124.2, 127.8, 128.0, 129.3, 134.5, 135.6, 138.9,
148.7, 152.5, 156.9, 159.4, 163.4, 169.0; ESI-MS: 396.7
(C20H14FN3O5, [M+H]+). Anal. calcd for C20H14FN3O5: C
60.76, H 3.57, N 10.63; found C 60.82, H 3.89, N 11.00.
In an effort to elucidate the mechanism by which the title
compound can induce anticancer activity in the human gas-
tric cell SGC-7901, molecular docking of the potent inhibitor
3b into binding site of telomerase was performed to simulate
a binding model derived from telomerase structure (3DU6.
pdb). The binding model of compounds 3b with telomerase
is depicted in Fig. (1).
3. Cytotoxic Assay
The cytotoxicity evaluation was conducted by using a
modified procedure. Briefly, target tumor cells were grown
to log phase in RPMI 1640 medium supplemented with 10%
fetal bovine serum. After diluting to 3ꢁ104 cells mL-1 with
the complete medium, 100 μL of the obtained cell suspen-
sion was added to each well of 96-well culture plates. The
subsequent incubation was performed at 37 ˚C, 5% CO2 at-
mosphere for 24 h before subjecting to cytotoxicity assess-
ment. Tested samples at pre-set concentrations were added to
6 wells with 5-fluorouracil co-assayed as a positive refer-
ence. After 48 h exposure period, 25 μL of PBS containing
2.5 mg mL-1 of MTT (3-(4, 5-dimethylthiazol-2-yl)-2, 5-
diphenyltetrazolium bromide) was added to each well. After
4h, the medium was replaced by 150 μL DMSO to dissolve
the purple formazan crystals produced. The absorbance at
570 nm of each well was measured on an ELISA plate
reader. The data represented the mean of three experiments
in triplicate and were expressed as means ±SD using Student
t test. The IC50 value was defined as the concentration at
which 50% of the cells could survive. The results are listed
in the Table 1.
CONCLUSIONS
In summary, we prepared a series of novel coumarin de-
rivatives containing 4,5-dihydropyrazole moiety as potential
telomerase inhibitors. The result showed that compound 3b
had potentially high activity against human gastric cancer
cell SGC-7901. Docking simulation was performed to posi-
tion compounds 3b into the telomerase 3DU6 active site.
The result showed compound 3b can bind well with the te-
lomerase active site and act as potential telomerase inhibitor.
ACKNOWLEDGEMENTS
The authors wish to thank the National Natural Science
Foundation of China (No.20902003); the Key Research

Synthesis and Anticancer Activity
Letters in Drug Design & Discovery, 2010, Vol. 7, No. 9 643
Ala-255
O
N
H
O
O
F
N
N
O
H3C
(A)
(B)
Fig. (1). Molecular docking modeling of compound 3b (A) with telomerase; the small molecule and the critical interaction of 3DU6 are rep-
resented by sticks. Panel is a view into the active site cavity. Compound 3b resides in a novel location, binds in a distinct manner among the
residues (140–343). They can bind well with the active site. An intramolecular hydrogen bond is observed between the N–H…..F: 2.31347 Å,
with amino hydrogen group of Ala-255. (B) Schematic representation of the binding mode of 3b in the ATP binding site of 3DU6.
phenylpyrazole derivatives. Bioorg. Med. Chem., 2008, 16, 881-
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(No.KJ2009A011Z).
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